Assessment of the Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT01147042
First received: June 17, 2010
Last updated: March 14, 2014
Last verified: January 2014
  Purpose

Background:

- Chronic granulomatous disease (CGD) is an immunodeficiency disease in which white blood cells are unable to kill certain bacteria and fungi. People with CGD are more likely to develop recurrent life-threatening infections. Certain changes or mutations in genes contribute to the severity of CGD, and also appear to affect the success of treatment with interferon-gamma, a substance that is used to improve the immune system s ability to fight infection. Researchers are interested in studying changes in the immune system caused by interferon-gamma treatment of CGD in individuals with different mutations that cause CGD.

Objectives:

- To compare changes in the immune system caused by interferon-gamma treatment for CGD in individuals with different mutations that cause CGD.

Eligibility:

- Individuals of any age who have been diagnosed with CGD and have specific types of mutations that cause CGD (to be determined after testing).

Design:

  • Participants will be screened with a medical history, physical examination, and blood and urine tests. Participants must weigh more than 11 kilograms (~24 pounds) to participate in the study.
  • Participants will receive injections of interferon-gamma once weekly for 4 weeks, twice weekly for 4 weeks, and then three times weekly for 4 weeks (a total of 24 injections).
  • Blood will be drawn periodically during treatment and for 8 weeks after the treatment, for a total of 21 weeks on the study. Participants will regularly provide information on their symptoms and responses to treatment to the study researchers.

Condition Intervention Phase
IFN-Gamma Therapy
CGD Gene Mutation
CGD Response to IFNg
Chronic Granulomatous Disease
Immunodeficiency Disease
Drug: IFN-gamma
Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Assessment of the Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The primary endpoint is the DHR assay, which measures superoxide production. [ Time Frame: 21 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The secondary endpoints are other assessments of immunologic function. [ Time Frame: 21 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 70
Study Start Date: May 2010
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: IFN-gamma
    N/A
Detailed Description:

Chronic Granulomatous Disease (CGD) is caused by mutations of 1 of the 4 proteins comprising the NADPH oxidase that result in decreased or absent production of superoxide by phagocytes, and predisposes CGD subjects to life-threatening infection. Intensive management with antibiotics and antifungal agents has dramatically increased the life expectancy of subjects with CGD. Interferon-gamma (IFN gamma), which increases superoxide production by neutrophils and enhances their antimicrobial activity, is an FDA approved therapy for CGD and is now the standard of care. However, there is substantial variability in the biochemical and clinical response to IFN gamma treatment. Recently, the specific mutations of the genes responsible for causing CGD in most of the subjects followed at the NIH have been characterized. Because of this, it is now known that the severity of the disease is correlated not only with inheritance pattern, but also with the specific underlying mutation. It is not known, however, if the biochemical response to IFN gamma therapy correlates with the specific mutation as well.

Since treatment with IFN gamma is expensive, requires frequent injections, and in some subjects results in systemic side effects, it would be useful to determine whether the biochemical response and systemic side effects correlate with the underlying mutation GCD.

We hypothesize that subjects with X-linked CGD due to nonsense/frameshift/RNA processing/deletion mutations of the gp91phox component of the NADPH oxidase will generate a smaller biochemical response to IFN gamma therapy compared to subjects with missense gp91phox mutations or the autosomal recessive form of CGD that results from mutations of the p47phox or p67phox components.

The primary objective of this study is to assess the predictability of IFN_F responsiveness in CGD based on mutational analysis. compare the change in function of the NADPH oxidase during treatment with an escalating dose of IFN_ompasubjects with CGD resulting from missense or nonsense/frameshift/RNA processing/deletion gp91phox mutations or mutations of p47phox or p67phox. The secondary objectives are to assess changes in superoxide production, expression of NADPH oxidase components, neutrophil bactericidal capacity for Staphyloccus aureus, cytokines, cell surface markers, antibodies, lymphocyte subsets, constitutional symptoms , and gene expression in leukocytes from subjects with missense gp91phox mutations, nonsense/frameshift/RNA processing/deletion gp91phox mutations, p47phox mutations, and p67phox mutations after treatment with IFN_R to assess changes in the expression of NADPH oxidase components, cytokines, cell surface markers, antibody production, production of various lymphocyte subsets, constitutional symptoms and gene expression in leukocytes from these subjects following treatment with IFNg. This knowledge will assist physicians in determining which subjects are likely to respond to full dose and alternative dose therapy with IFNg and provide information about biochemical responses of to these regimens in subjects with specific CDG gene mutations enabling them to better counsel and manage subjects with CGD.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Subjects may be enrolled if they are:

  1. Already are enrolled on an existing CGD protocol at the Clinical Center (and will remain enrolled on their existing protocol);
  2. Are included in one of the study cohorts listed below;
  3. Male or female;
  4. Able to comply with self-administration of a subcutaneous injection; and
  5. Willing to have their blood samples stored for the duration of this study and for future research.

Study Groups/Cohorts:

X-linked CGD Nonsense/Frameshift/RNA Processing/Deletion Mutations Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented nonsense, frameshift, RNA processing, or deletion gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

X-linked CGD Missense Mutation with Low Baseline Superoxide Production (less than or equal to 2.5 nmol/10(6) cells/hr) Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented missense gene and superoxide production by cytochrome c reduction assay at baseline of less than or equal to 2.5 nmol/10(6) cells/hr. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

X-linked CGD Missense Mutation with Higher Baseline Superoxide Production (greater than 2.5 nmol/10(6) cells/hr) Cohort: Subjects in this cohort must have X-linked CGD resulting from a documented missense gene and superoxide production by cytochrome c reduction assay at baseline of greater than 2.5 nmol/10(6) cells/hr. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

Autosomal Recessive p47phox CGD Cohort: Subjects in this cohort must have autosomal recessive CGD resulting from a documented p47phox gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

Autosomal Recessive p67phox CGD Cohort: Subjects in this cohort must have autosomal recessive CGD resulting from a documented p67phox gene mutation. Subjects with other gene defects or for whom the specific genetic defect has not been determined are not eligible for inclusion in this cohort.

EXCLUSION CRITERIA:

Subjects are excluded from the study who:

  1. Have undergone successful bone marrow transplantation;
  2. Had a serious adverse reaction to IFN gamma in the past;
  3. Are pregnant or breast feeding;
  4. Weigh less than 11 kg;
  5. Are currently on therapy with INF gamma;
  6. Have any of the following medical conditions:

    • Coronary artery disease;
    • Hepatic disease and/or liver enzymes elevated above 3 times normal;
    • Seizure disorder, or
    • Severe myelosuppression (absolute neutrophil count less than1000 cells/mm(3)).

Participation of Minors: minor patients will be invited to participant in this study.

Participation of Women: Exposure to IFN gamma by the developing human fetus may be detrimental. For this reason, women of childbearing-age will have a pregnancy test prior to undergoing study procedures. Should a woman become pregnant or suspect that she is pregnant while participating in this study, she should immediately inform study staff and her primary care physician.

Pregnancy and Lactation: The effects of IFN gamma therapy on the developing fetus and newborn infant have not been studied. Therefore, it is not recommended that subjects who are pregnant or breast-feeding receive IFN gamma and they will be excluded from this study.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01147042

Contacts
Contact: Patricia L Littel, R.N. (301) 402-5964 plittel@cc.nih.gov
Contact: John I Gallin, M.D. (301) 496-4114 jgallin@cc.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: John I Gallin, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT01147042     History of Changes
Other Study ID Numbers: 100123, 10-I-0123
Study First Received: June 17, 2010
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
NADPH Oxidase
CGD
Gene Mutation
Superoxide by Phagocytes
IFN-Gamma
Chronic Granulomatous Disease

Additional relevant MeSH terms:
Granulomatous Disease, Chronic
Granuloma
Immunologic Deficiency Syndromes
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Hematologic Diseases
Immune System Diseases
Leukocyte Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Pathologic Processes
Phagocyte Bactericidal Dysfunction
Interferon-gamma
Anti-Infective Agents
Antiviral Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014